Regulation of eIF2 activity
Eukaryotic translation initiation factors (eIF2) is a
G-protein that is composed of 3 non-identical subunits,
and eIF2S3, and catalyzes the first regulated
step of protein synthesis initiation, promoting the binding of the initiator tRNA to 40S
ribosomal subunits. Phosphorylation of eIF2S1 modulates rate
of formation of the complex eIF2/GTP/tRNA .
Key pathways of eIF2 activity regulation are
phosphorylation of eIF2S1 and phosphorylation of Eukaryotic
initiation factor 2 (eIF2B) by some protein kinases.
Four distinct protein kinases inhibit protein synthesis in eukaryotic cells via
phosphorylation of eIF2S1 at serine-51. There are Eukaryotic
translation initiation factor 2-alpha kinase 1, 2, 3 and 4
EIF2AK3 and GCN2), that belong
to the serine/threonine family of protein kinases. Phosphorylation of
eIF2S1 results in shutdown of protein synthesis.
EIF2AK1 is activated under conditions of heme deficiency,
predominantly in immature erythroid cells, and its activity is inhibited by heme .
PKR acts as an antiviral machinery of type I Interferons.
Expression of PKR is induced by interferon, and its kinase
activity is stimulated by low concentrations of double-stranded RNA.
PKR-mediated inhibition is neutralizated via direct
dephosphorylation and monomerization of PKR by Alpha
catalytic subunit protein phosphatase 1 (PP1) . Also, PP1 can dephosphorylates
eIF2S1 thereby activating eIF2 formation
EIF2AK3 is activated under conditions of Endoplasmic
reticulum (ER) stress. ER stress is caused by unfolded or misfolded proteins, which are
accumulared by extracellular or intracellular stimuli .
GCN2 is activated by amino acid starvation
phosphorylates. GCN2 inhibites
EIF2S1. It is one of the eukaryotic initiation factors that
have a role in eukaryotic peptide chain initiation process .
Exchange of GDP for GTP on eIF2 is stimulated by
eIF2B. eIF2B is a heteromeric
guanine nucleotide exchange factor that plays an important role in regulating mRNA
translation. It is composed of 5 subunits termed eIF2B1-5 in
order of increasing size .
eIF2B has multiple phosphorylation sites in the largest,
catalytic, subunit eIF2B5.
Kinases, which phosphorylate of the eIF2B5-subunit of
eIF2B, are Casein kinase I and
II, Glycogen synthase kinase 3 alpha and beta isoforms
(GSK3 alpha/beta), and Dual specificity
tyrosine-phosphorylated and -regulated kinases (DYRK1a and
DYRK2). elF2B5 phosphorylation
by casein kinases enhances
eIF2B activity, whereas phosphorylation by
GSK3 has an inhibitory effect .
Phosphorylation by GSK3 requires previous
elF2B5 phosphorylation that is catalyzed by
Phosphotase PP1 deviates inhibitory effect of
GSK3 via dephosphorilation of
eIF2B . Activity of
PP1 and GSK3 is regulated by
different extracellular stimulus.
For example, Insulin receptor and Epidermal growth factor
receptor (EGFR) activate the enzymatic activity of
Phosphatidylinositol 3-kinase class I via recruitment of regulatory subunit
(PI3K reg) either directly or via adaptor proteins (e.g.
Insulin receptor substrates 1 and 2 (IRS-1 and
IRS-2), GRB2-associated binding protein 1
(GAB1) or Signal transduction protein CBL
(c-Cbl)) , , .
Active Phosphatidylinositol 3-kinase class I catalytic (PI3K
cat) converts Phosphatidylinositol 4,5-biphosphate
(PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate
PtdIns(3,4,5)P3 is a second messenger. It recruits and
activates V-akt murine thymoma viral oncogene homolog 1
(AKT) and Phosphoinositide dependent protein kinase-1
(PDK) to membrane via PH domain .AKT, in turn, negatively regulates
GSK3 by phosphorylation thereby abrogate inhibitory effect
GSK3 to eIF2B activity , .
Also EGFR induces MAPK
cascade. It was shown, that MEK/ Mitogen-activated protein
kinase (ERK) pathway is required for activation of
eIF2B. It was suggested that the active ERK
activates phosphotase PP1. This
leads to activation of eIF2B .
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